More than 40,000 women die of metastatic breast cancer annually in the United States alone. Among the several subtypes of breast cancer, those classified as triple negative breast cancer (TNBC) are especially lethal due to their high metastatic potential and likely rapid recurrence. TNBC is characterized by the lack of expression of hormone receptors specifically ER-? and PR, and the absence of overexpression of human epidermal growth factor receptor 2 (HER2). Therapies that target ER and HER2 are generally not effective against TNBC. There is no FDA-approved targeted therapy for TNBC and clinicians entirely rely on cytotoxic agents for tumor control. There is a clear need to develop effective targeted therapies for TNBC. The Bromodomain and Extra Terminal (BET) family of proteins, consisting of BRD2, BRD3, BRD4 and BRDT, are epigenetic ?readers? and play a key role in epigenetic regulation of gene transcription. BET proteins, in particular BRD4, have emerged as exciting new therapeutic targets for several human diseases and conditions. Recent studies have suggested that BET proteins are exciting new targets for TNBC. In this R01 project, we propose to design, synthesize and develop highly potent small-molecule ?degraders? of BET proteins as a new class of therapies for TNBC and to elucidate their mechanism of action. In contrast to small-molecule BET inhibitors, which bind to BET proteins and block their interactions with histone tails, small-molecule BET degraders bind to BET proteins and induce their rapid degradation in cells and tissues. Our preliminary data have shown that our small-molecule BET degraders effectively induce degradation of BET proteins in TNBC cancer cells at concentrations of 1-3 nM and achieve IC50 values of <10 nM in the majority of human TNBC cancer cell lines tested. In direct comparison, our small-molecule BET degraders are >100-times more potent than our most potent BET inhibitors in inhibition of cancer cell growth and much more effective in induction of apoptosis in cancer cells. A single dose of a BET degrader effectively induces degradation of BRD4 protein in tumor tissue. In vivo efficacy testing showed that our BET degraders are very effective in inhibition of tumor growth in a TNBC patient-derived xenograft model and a xenograft model of TNBC cell line in mice and are well tolerated in animals. Based upon these exciting preliminary data, we propose to perform extensive optimization and testing of our promising small-molecule BET degraders for their therapeutic potential and mechanism of action for the treatment of TNBC. Our goal is to select one or more highly potent and optimized BET degrader for advanced preclinical development for the treatment of TNBC.